Injectable Capsaicin for the Management of Pain Due to Osteoarthritis.

Capsaicin is a potent agonist of the TRPV1 channel, a transduction channel that is highly expressed in nociceptive fibers (pain fibers) throughout the peripheral nervous system. Given the importance of TRPV1 as one of several transduction channels in nociceptive fibers, much research has been focused on the potential therapeutic benefits of using TRPV1 antagonists for the management of pain. However, an antagonist has two limitations. First, an antagonist in principle generally only affects one receptor. Secondly, most antagonists must have an ongoing presence on the receptor to have an effect. Capsaicin overcomes both liabilities by disrupting peripheral terminals of nociceptive fibers that express TRPV1, and thereby affects all of the potential means of activating that pain fiber (not just TRPV1 function). This disruptive effect is dependent on the dose and can occur within minutes. Thus, unlike a typical receptor antagonist, continued bioavailability at the level of the receptor is not necessary. By disrupting the entire terminal of the TRPV1-expressing nociceptive fiber, capsaicin blocks all the activation mechanisms within that fiber, and not just TRPV1 function. Topical capsaicin, an FDA approved treatment for neuropathic pain, addresses pain from abnormal nociceptor activity in the superficial layers of the skin. Effects after a single administration are evident over a period of weeks to months, but in time are fully reversible. This review focuses on the rationale for using capsaicin by injection for painful conditions such as osteoarthritis (OA) and provides an update on studies completed to date.

Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1.

Capsaicin is an ingredient in spicy peppers that produces burning pain by activating transient receptor potential vanilloid 1 (TRPV1), a Ca2+-permeable ion channel in nociceptors. Capsaicin has also been used as an analgesic, and its topical administration is approved for the treatment of certain pain conditions. The mechanisms underlying capsaicin-induced analgesia likely involve reversible ablation of nociceptor terminals. However, the mechanisms underlying these effects are not well understood. To visualize TRPV1-lineage axons, a genetically engineered mouse model was used in which a fluorophore is expressed under the TRPV1 promoter. Using a combination of these TRPV1-lineage reporter mice and primary afferent cultures, we monitored capsaicin-induced effects on afferent terminals in real time. We found that Ca2+ influx through TRPV1 is necessary for capsaicin-induced ablation of nociceptive terminals. Although capsaicin-induced mitochondrial Ca2+ uptake was TRPV1-dependent, dissipation of the mitochondrial membrane potential, inhibition of the mitochondrial transition permeability pore, and scavengers of reactive oxygen species did not attenuate capsaicin-induced ablation. In contrast, MDL28170, an inhibitor of the Ca2+-dependent protease calpain, diminished ablation. Furthermore, overexpression of calpastatin, an endogenous inhibitor of calpain, or knockdown of calpain 2 also decreased ablation. Quantitative assessment of TRPV1-lineage afferents in the epidermis of the hind paws of the reporter mice showed that EGTA and MDL28170 diminished capsaicin-induced ablation. Moreover, MDL28170 prevented capsaicin-induced thermal hypoalgesia. These results suggest that TRPV1/Ca2+/calpain-dependent signaling plays a dominant role in capsaicin-induced ablation of nociceptive terminals and further our understanding of the molecular mechanisms underlying the effects of capsaicin on nociceptors.

individual variation in sleep quality and duration is related to cerebral mu opioid receptor binding potential during tonic laboratory pain in healthy subjects.

OBJECTIVE: Although poor sleep is a consequence of pain, sleep disturbance reciprocally induces hyperalgesia and exacerbates clinical pain. Conceptual models of chronic pain implicate dysfunctional supraspinal pain processing mechanisms, mediated in part by endogenous opioid peptides. Our preliminary work indicates that sleep disruption impairs psychophysical measures of descending pain modulation, but few studies have investigated whether insufficient sleep may be associated with alterations in endogenous opioid systems. This preliminary, exploratory investigation sought to examine the relationship between sleep and functioning of the cerebral mu opioid system during the experience of pain in healthy participants. SUBJECTS AND DESIGN: Twelve healthy volunteers participated in a 90-minute positron emission tomography imaging scan using [11C]Carfentanil, a mu opioid receptors agonist. During the session, pain responses to a 10% topical capsaicin cream were continuously rated on a 0-100 scale. Participants also completed the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Poor sleep quality (PSQI) was positively and significantly associated with greater binding potential (BP) in regions within the frontal lobes. In addition, sleep duration was negatively associated with BP in these areas as well as the temporal lobe and anterior cingulate. CONCLUSIONS: These findings suggest that poor sleep quality and short sleep duration are associated with endogenous opioid activity in these brain regions during the application of a noxious stimulus. Elucidating the role of the endogenous opioid system in mediating some of the associations between sleep and pain could significantly improve our understanding of the pathophysiology of chronic pain and might advance clinical practice by suggesting interventions that could buffer the adverse effects of poor sleep on pain.

A new program in pain medicine for medical students: integrating core curriculum knowledge with emotional and reflective development.

OBJECTIVE: Improvements in clinical pain care have not matched advances in scientific knowledge, and innovations in medical education are needed. Several streams of evidence indicate that pain education needs to address both the affective and cognitive dimensions of pain. Our aim was to design and deliver a new course in pain establishing foundation-level knowledge while comprehensively addressing the emotional development needs in this area. SETTING: One hundred eighteen first-year medical students at Johns Hopkins School of Medicine. OUTCOME MEASURES: Performance was measured by multiple-choice tests of pain knowledge, attendance, reflective pain portfolios, and satisfaction measures. RESULTS: Domains of competence in pain knowledge included central and peripheral pain signalling, pharmacological management of pain with standard analgesic medications, neuromodulating agents, and opioids; cancer pain, musculoskeletal pain, nociceptive, inflammatory, neuropathic, geriatric, and pediatric pain. Socio-emotional development (portfolio) work focused on increasing awareness of pain affect in self and others, and on enhancing the commitment to excellence in pain care. Reflections included observations on a brief pain experience (cold pressor test), the multidimensionality of pain, the role of empathy and compassion in medical care, the positive characteristics of pain-care role models, the complex feelings engendered by pain and addiction including frustration and disappointment, and aspirations and commitments in clinical medicine. The students completing feedback expressed high levels of interest in pain medicine as a result of the course. DISCUSSION: We conclude that a 4-day pain course incorporating sessions with pain specialists, pain medicine knowledge, and design-built elements to strengthen emotional skills is an effective educational approach. SUMMARY: Innovations in medical education about pain are needed. Our aim was to design and deliver a new course for medical students addressing both the affective and cognitive dimensions of pain. Combining small-group sessions with pain specialists, active-learning approaches to pain knowledge, and design-built elements to strengthen emotional skills was highly effective.

Fight fire with fire: Neurobiology of capsaicin-induced analgesia for chronic pain.

Capsaicin, the pungent ingredient in chili peppers, produces intense burning pain in humans. Capsaicin selectively activates the transient receptor potential vanilloid 1 (TRPV1), which is enriched in nociceptive primary afferents, and underpins the mechanism for capsaicin-induced burning pain. Paradoxically, capsaicin has long been used as an analgesic. The development of topical patches and injectable formulations containing capsaicin has led to application in clinical settings to treat chronic pain conditions, such as neuropathic pain and the potential to treat osteoarthritis. More detailed determination of the neurobiological mechanisms of capsaicin-induced analgesia should provide the logical rationale for capsaicin therapy and help to overcome the treatment's limitations, which include individual differences in treatment outcome and procedural discomfort. Low concentrations of capsaicin induce short-term defunctionalization of nociceptor terminals. This phenomenon is reversible within hours and, hence, likely does not account for the clinical benefit. By contrast, high concentrations of capsaicin lead to long-term defunctionalization mediated by the ablation of TRPV1-expressing afferent terminals, resulting in long-lasting analgesia persisting for several months. Recent studies have shown that capsaicin-induced Ca2+/calpain-mediated ablation of axonal terminals is necessary to produce long-lasting analgesia in a mouse model of neuropathic pain. In combination with calpain, axonal mitochondrial dysfunction and microtubule disorganization may also contribute to the longer-term effects of capsaicin. The analgesic effects subside over time in association with the regeneration of the ablated afferent terminals. Further determination of the neurobiological mechanisms of capsaicin-induced analgesia should lead to more efficacious non-opioidergic analgesic options with fewer adverse side effects.

Mechanisms of neuropathic pain.

Neuropathic pain refers to pain that originates from pathology of the nervous system. Diabetes, infection (herpes zoster), nerve compression, nerve trauma, "channelopathies," and autoimmune disease are examples of diseases that may cause neuropathic pain. The development of both animal models and newer pharmacological strategies has led to an explosion of interest in the underlying mechanisms. Neuropathic pain reflects both peripheral and central sensitization mechanisms. Abnormal signals arise not only from injured axons but also from the intact nociceptors that share the innervation territory of the injured nerve. This review focuses on how both human studies and animal models are helping to elucidate the mechanisms underlying these surprisingly common disorders. The rapid gain in knowledge about abnormal signaling promises breakthroughs in the treatment of these often debilitating disorders.

Improving Study Conduct and Data Quality in Clinical Trials of Chronic Pain Treatments: IMMPACT Recommendations.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

Randomized, Double-Blind, Placebo-Controlled Trial of Intraarticular Trans-Capsaicin for Pain Associated With Osteoarthritis of the Knee.

OBJECTIVE: To assess the efficacy and safety of high-purity synthetic trans-capsaicin (CNTX-4975) in patients with chronic moderate-to-severe osteoarthritis (OA)-associated knee pain. METHODS: In this phase II multicenter double-blind study, patients ages 45-80 years who had stable knee OA were randomized in a 2:1:2 ratio to receive a single intraarticular injection of placebo, CNTX-4975 0.5 mg, or CNTX-4975 1.0 mg. The primary efficacy end point was area under the curve (AUC) for change from baseline in daily Western Ontario and McMaster Universities Osteoarthritis Index pain with walking score (range 0-10, 0 = none and 10 = extreme) through week 12. Secondary efficacy end points included a similar AUC analysis of outcomes in patients treated with CNTX-4975 0.5 mg, and evaluations extending to 24 weeks. RESULTS: Efficacy was evaluated in 172 patients (placebo group, n = 69; CNTX-4975 0.5 mg group, n = 33; CNTX-4975 1.0 mg group, n = 70). At week 12, greater decreases in the AUC for the pain score were observed with CNTX-4975 in the 0.5 mg and 1.0 mg groups versus placebo (0.5 mg group least squares mean difference [LSMD] -0.79, P = 0.0740; 1.0 mg group LSMD -1.6, P < 0.0001). Significant improvements were maintained at week 24 in the 1.0 mg group (LSMD -1.4, P = 0.0002). Treatment-emergent adverse events were similar in the placebo and CNTX-4975 1.0 mg groups. CONCLUSION: In this study, CNTX-4975 provided dose-dependent improvement in knee OA-associated pain. CNTX-4975 1.0 mg produced a significant decrease in OA knee pain through 24 weeks; CNTX-4975 0.5 mg significantly improved pain at 12 weeks, but the effect was not evident at 24 weeks.

Use of Capsaicin to Treat Pain: Mechanistic and Therapeutic Considerations.

Capsaicin is the pungent ingredient of chili peppers and is approved as a topical treatment of neuropathic pain. The analgesia lasts for several months after a single treatment. Capsaicin selectively activates TRPV1, a Ca2+-permeable cationic ion channel that is enriched in the terminals of certain nociceptors. Activation is followed by a prolonged decreased response to noxious stimuli. Interest also exists in the use of injectable capsaicin as a treatment for focal pain conditions, such as arthritis and other musculoskeletal conditions. Recently injection of capsaicin showed therapeutic efficacy in patients with Morton's neuroma, a painful foot condition associated with compression of one of the digital nerves. The relief of pain was associated with no change in tactile sensibility. Though injection evokes short term pain, the brief systemic exposure and potential to establish long term analgesia without other sensory changes creates an attractive clinical profile. Short-term and long-term effects arise from both functional and structural changes in nociceptive terminals. In this review, we discuss how local administration of capsaicin may induce ablation of nociceptive terminals and the clinical implications.

A randomized, double-blind, placebo-controlled trial of injected capsaicin for pain in Morton's neuroma.

Intermetatarsal neuroma or Morton's neuroma is a painful condition of the foot resulting from an entrapment of the common digital nerve typically in the third intermetatarsal space. The pain can be severe and especially problematic with walking. Treatment options are limited and surgery may lead to permanent numbness in the toes. Capsaicin, the pungent ingredient of hot peppers, produces analgesia by inducing retraction of nociceptive afferents from the area of innervation and is effective in treating certain neuropathic pain disorders. A randomized double-blind placebo-controlled study was conducted to test the efficacy, tolerability, and safety of a single 0.1 mg dose of capsaicin vs placebo injected into the region of the neuroma. A total of 58 subjects diagnosed with Morton's neuroma with foot pain ≥4 (0-10 numerical pain rating scale) were injected with 2 mL of lidocaine into the intermetatarsal space proximal to the neuroma to provide local anesthesia. After 5 minutes, 0.1 mg capsaicin or placebo was injected into the intermetatarsal space containing the painful neuroma. Average foot pain was rated for 2 weeks before through 4 weeks after injection. At weeks 1 and 4, the decrease in pain was significantly greater in the subjects treated with capsaicin (P = 0.021 and P = 0.019, respectively). A trend toward significance was noted at weeks 2 and 3. Improvements in functional interference scores and reductions in oral analgesic use were also seen in the capsaicin-treated group. These findings suggest that injection of capsaicin is an efficacious treatment option for patients with painful intermetatarsal neuroma.

Fatigue and paradoxical enhancement of heat response in C-fiber nociceptors from cross-modal excitation.

Fatigue refers to the decrement of response seen with repeated stimulation and is a prominent attribute of nociceptors. Whether fatigue in nociceptors involves transduction, spike initiation, or conduction mechanisms is unknown. We investigated systematically how electrical, mechanical, and heat conditioning stimuli (eCS, mCS, hCS) affected the subsequent response to a test-heat stimulus applied 5 sec later to the receptive field of cutaneous nociceptors. Standard teased-fiber techniques were used to record from mechano-heat-sensitive C-fiber afferents in the anesthetized monkey. The eCS was applied to the nerve trunk, whereas the hCS and mCS were applied to the heat-test site. For the eCS, the number of pulses rather than frequency of stimulation determined the level of fatigue. Fatigue varied inversely with the time interval between the eCS and the test stimulus. For comparable responses from the CS, the magnitude of fatigue was less after the mCS than after the eCS. The mCS (but not the eCS) sometimes evoked a paradoxical increase in response to the test-heat stimulus. Recovery from fatigue was significantly faster after the eCS and mCS than the hCS. The paradoxical enhancement after the mCS probably results from temporal summation of generator potentials produced by mechanical and heat stimulation and suggests that the time constant of the generator potential is on the order of seconds. Concurrent enhancement-fatigue effects may also explain why fatigue was less after the mCS than the eCS. The dependency of recovery from fatigue on the modality of the CS suggests that fatigue results from transduction-spike initiation mechanisms.

The population response of A- and C-fiber nociceptors in monkey encodes high-intensity mechanical stimuli.

The peripheral neural mechanism of pain to mechanical stimuli remains elusive. C-fiber nociceptors do not appear to play a major role in mechanical pain sensation, because the stimulus-response function of mechanically sensitive C-fiber nociceptors to punctate mechanical stimuli applied to the most sensitive region in the receptive field (the hot spot) reaches a plateau at force levels insufficient to produce pain in humans. However, studies at the hot spot give an incomplete understanding of the inputs of nociceptors to the spinal cord. To estimate how the population of nociceptors responds to a punctate stimulus, it is necessary to know how the response varies with the position within the receptive field. For A-fiber and C-fiber nociceptors, we systemically measured the response to a 100 microm wide blade stimulus as a function of position in the receptive field at different force levels. Highly reproducible receptive field response maps that contained multiple peaks and valleys were obtained. Some peaks were only 100 microm wide. As force increased, the response and width of the peaks increased, the response in valleys increased, and new peaks appeared. The averaged response across the map provides an estimate of the population response and was found to increase monotonically with force over a large stimulus range for both A-fiber and C-fiber nociceptors. These data provide evidence that both C-fiber and A-fiber nociceptors may encode high-intensity mechanical stimuli.

Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents.

We demonstrated recently that uninjured C-fiber nociceptors in the L4 spinal nerve develop spontaneous activity after transection of the L5 spinal nerve. We postulated that Wallerian degeneration leads to an alteration in the properties of the neighboring, uninjured afferents from adjacent spinal nerves. To explore the role of degeneration of myelinated versus unmyelinated fibers, we investigated the effects of an L5 ventral rhizotomy in rat. This lesion leads to degeneration predominantly in myelinated fibers. Mechanical paw-withdrawal thresholds were assessed with von Frey hairs, and teased-fiber techniques were used to record from single C-fiber afferents in the L4 spinal nerve. Behavioral and electrophysiological data were collected in a blinded manner. Seven days after surgery, a marked decrease in withdrawal thresholds was observed after the ventral rhizotomy but not after the sham operation. Single fiber recordings revealed low-frequency spontaneous activity in 25% of the C-fiber afferents 8-10 d after the lesion compared with only 11% after sham operation. Paw-withdrawal thresholds were inversely correlated with the incidence of spontaneous activity in high-threshold C-fiber afferents. In normal animals, low-frequency electrocutaneous stimulation at C-fiber, but not A-fiber, strength produced behavioral signs of secondary mechanical hyperalgesia on the paw. These results suggest that degeneration in myelinated efferent fibers is sufficient to induce spontaneous activity in C-fiber afferents and behavioral signs of mechanical hyperalgesia. Ectopic spontaneous activity from injured afferents was not required for the development of the neuropathic pain behavior. These results provide additional evidence for a role of Wallerian degeneration in neuropathic pain.

Surgical treatment of thoracic outlet syndrome: a randomized trial comparing two operations.

OBJECT: Various surgical approaches have been proposed for the treatment of thoracic outlet syndrome (TOS). The authors of this study focused on the differences in outcome after supraclavicular neuroplasty of brachial plexus (SNBP [no rib resection]) and transaxillary first rib resection (TFRR) in patients in whom the dominant clinical problem was pain. METHODS: Fifty-five patients were randomized to undergo TFRR or SNBP. Patients with an anomalous cervical rib, intrinsic weakness, and primarily vascular findings were excluded from the study. Preoperatively, the following findings were typically observed: provocation of symptoms by certain postures (the so-called spear-throwing position as well as downward tugging of the shoulder) and marked tenderness in the supraclavicular fossa. The intergroup severity of the symptoms was comparable. Eight patients were lost to follow up. There were 24 TFRRs (in two cases the procedure was bilateral) and 25 SNBPs. The mean follow-up interval was 37 months. In both groups pain decreased significantly after surgery. By all measures the TFRR operation conferred superior results. Patients reported significantly less pain (39 +/- 7 compared with 61 +/- 7; score range 0-100 on a visual analog scale), greater percentage of pain relief (52 +/- 8% compared with 30 +/- 7%), and less pain (3.7 +/- 0.4 compared with 5.1 +/- 0.5) on an affective scale (all p < 0.05) in the TFRR and SNBP groups, respectively). In the TFRR group, 75% of patients reported good or excellent outcomes compared with 48% in the SNBP group (p < 0.05). CONCLUSIONS: Transaxillary first rib resection provided better relief of symptoms than SNBP. The major compressive element in patients with TOS-associated pain appeared to be the first rib.

Naloxone does not affect pain relief induced by electrical stimulation in man.

We wished to determine if pain relief that resulted from transcutaneous (TNS) or spinal cord electrical stimulation in patients with chronic pain was due to activation of an endogenous opiate-related pain control system. Naloxone (0.4-10 mg) or saline was injected in double-blind fashion intravenously into opiate-naive subjects with chronic pain who achieved 30% or greater pain relief with spinal cord stimulation (4 patients) or TNS (9 patients). Subjects rated their pain during stimulation and 2, 5, 10 and 15 min after the injection. Two days or more later the procedure was repeated using the alternate agent (naloxone or saline). Naloxone did not decrease the pain relief induced by stimulation, and therefore the effects of stimulation are probably not mediated by the endogenous opiates.

Monitoring adequacy of alpha-adrenoceptor blockade following systemic phentolamine administration.

Systemic phentolamine administration has been suggested as a diagnostic tool for identifying patients with sympathetically maintained pain (SMP) (Raja et al. 1991). The dose of phentolamine to produce adequate blockade of peripheral alpha-adrenoceptor function has, however, not been previously determined. In this study, the effects of two different doses of phentolamine on peripheral sympathetic vasoconstrictor function were investigated. One-hundred and seventeen (117) patients with chronic extremity pain underwent 130 phentolamine diagnostic tests using two different doses of phentolamine (0.5 mg/kg over 20 min (n = 60) and 1 mg/kg over 10 min (n = 59)). Eleven (11) patients did not receive phentolamine during the test. Cutaneous temperature was measured in the distal extremity before and after administration of phentolamine. In a subset of patients, baseline blood flow and sympathetically mediated vasoconstrictor response (SMR) to deep inhalation were measured on glabrous skin using laser Doppler flowmetry. SMR was elicited with a 5-sec maximal inspiratory gasp. A dose-related increase in cutaneous temperature was observed. In addition, baseline blood flow increased and SMR was attenuated after both doses of phentolamine, but to a greater degree after the 1 mg/kg dose. However, SMR was not completely attenuated, even after administration of the higher phentolamine dose. These results indicate that a phentolamine dose of 1 mg/kg over 10 min more completely blocks alpha-adrenoceptor function than a dose of 0.5 mg/kg over 20 min. We therefore recommend that to ensure adequate alpha-adrenoceptor blockade the higher phentolamine dose be used in the phentolamine diagnostic test for SMP.

Responses to heat of C-fiber nociceptors in monkey are altered by injury in the receptive field but not by adjacent injury.

We sought to determine the effects of a cut injury on the thermal responsiveness of C-fiber nociceptors sensitive to heat and mechanical stimuli (CMHs). Teased fiber techniques were used to record from single CMHs that innervated the hairy skin of the monkey arm. Responses to heat stimuli ranging from 41 to 49 degrees C were compared before and after injury. In 11 CMHs, the injury was applied 4 mm peripheral to the edge of the receptive field. The response to the heat sequence was not significantly altered by this adjacent injury. In 16 CMHs, a cut was applied directly to the receptive field. This direct injury led to a significant increase in response to the sequence of heat stimuli (i.e., sensitization). It is concluded that spreading sensitization of C-fiber nociceptors to a cut injury does not occur in monkey.

Myelinated afferents signal the hyperalgesia associated with nerve injury.

Pain to light touching of the skin is a hallmark sign of causalgia. The purpose of this study was to determine whether myelinated or unmyelinated afferent fibers signal this hyperalgesia. Sensory testing was performed in 17 patients with long-standing hyperalgesia after nerve injury. The patients underwent a differential ischemic block of nerve function of the involved area. At a time when touch sensation in adjacent normal skin was eliminated, but when sensibility to warming and cooling stimuli was unaffected, the hyperalgesia to mechanical stimuli was abolished in 15 of the subjects. In 2 of these 15 patients, a differential local anesthetic block of the injured nerve was performed proximal to the site of injury. When temperature sensibility was absent, but when touch sensation was intact, hyperalgesia was present. In a third study, latency measurements in response to 400 micron stepped displacement stimuli were made in two patients who had hyperalgesia on the foot. The mean latency for detection of pain in the hyperalgesic region was 414 +/- 18 msec, compared to 458 +/- 16 msec for the detection of touch to the same stimuli applied to the opposite normal foot. These 3 lines of evidence indicate that myelinated primary afferents, perhaps A beta fibers, signal the hyperalgesic pain in causalgia. These fibers may be sensitized A beta nociceptors or low-threshold mechanoreceptors.